Cell-to-cell transmission of viruses

Abstract

The life cycle of most viruses involves the release of particles into the extracellular space. Consequently, the study of virus egress as well as virus entry has focused almost exclusively on the biology of cell-free virus. However, cell-free virus spread is often very inefficient. Specific barriers, either located in the donor cell or in the target cell, prevent efficient spread by the cell-free mode. In contrast, viral spread by direct cell-cell contact is largely unaffected by most of these barriers resulting in preferential spread by cell-to-cell transmission. Virus cell-to-cell transmission allows an efficient coordination of several steps of the viral life cycle. It often involves complex inter-cellular adhesion, cellular polarity and intra-cellular trafficking. Because virus cell-to-cell transmission can involve transmission through zones of tight cell-cell contact that are resistant to neutralizing antibodies and reach a high local particle concentration, cell-to-cell transmission can contribute to the pathogenesis of viral infections.

Figure 1

Virus cell-to-cell transmission enhances viral spreading to target cells. (a) Virus spreading by 3-dimensional diffusion creates a concentration gradient around the infected cell. The probability of a viral particle released from the infected cell (blue) to reach the target cell (green) is dependent on the travel distance and the travel time. Adjacent cells would be more efficiently infected, but distant cells can be reached with sufficient time. (b) Retention of particles on the surface of the donor cell interferes with viral spread by diffusion, but increases the local concentration of viral particles and as such increases the probability of infection of contacting neighboring target cells. Thus, any mechanism promoting cell surface retention combined with cell-cell adhesion can enhance the efficiency of viral spreading to contacting cells. (c) Virus cell-to-cell transmission becomes most efficient when particles are also polarized to the site of cell-cell contact. A mechanism involving cell-cell adhesion and polarity leads to the most efficient viral spread. The two target cells illustrate the trade-off between long-range diffusion and highly efficient local viral spread between contacting cells.

Figure 2

Viruses evolved to utilize existing cell-cell contacts for efficient viral spreading or, alternatively, are able to deliberately establish new cell-cell contacts between the infected cell (blue) and the target cell (green). (a) Neurotropic viruses can highjack bidirectional microtubule-mediated transport in neurons to spread from one neuron to another [44]. (b) Viruses can also promote long-lived cell-cell contact between cells that typically do not engage in prolonged contacts such as T lymphocytes. Transmission can occur (I) when particles are retained on the surface of the infected cell [15,21], which then comes into contact with an uninfected cell, (II) by surface movement of assembled particles toward the site of cell-cell contact [,–42], or (III) by polarization of de novo viral assembly at the site of cell-cell contact [20].

Figure 3

Cell biology of viral spreading (I). Viral particles can be transmitted by (a) cell-free dissemination through the extracellular space [1,4] or at sites of cell-cell contact (b, c). In both cases, viruses can be released from the cell surface and enter target cells directly at the cell surface [20,27,40]. Alternatively, viruses can also assemble into vesicles that are released by fusion at the plasma membrane and enter target cells by endocytosis prior to delivery into the cytoplasm [28,37,41,43 ].

Figure 4

Cell biology of viral spreading (II). The utilization of inter-cellular membrane bridges. (a, b) In addition to cell-free spread, viruses can remain associated with the surface of the infected cell and spread across long filopodial bridges that connect donor and target cells [21,36,51]. (c) Vaccinia virus remains associated with the producer cell to polymerize actin to propel itself towards neighboring cells [6]. (d) Cytosol-to-cytosol connectivity can promote the transmission of viral genomes or viral capsids [7]. (e) Viral particles may also be transferred across cytoplasmic connections within vesicles [53].